After oral administration of radiolabelled nefazodone, the mean half-life of total label ranged between 11 and 24 hours. Approximately 55% of the administered radioactivity was detected in urine and about 20-30% in feces.

Distribution - Nefazodone is widely distributed in body tissues, including the central nervous system (CNS). In humans the volume of distribution of nefazodone ranges from 0.22 to 0.87 L/kg.

Protein Binding - At concentrations of 25-2500 ng/mL nefazodone is extensively (>99%) bound to human plasma proteins in vitro. The administration of 200 mg BID of nefazodone for 1 week did not increase the fraction of unbound warfarin in subjects whose prothrombin times had been prolonged by warfarin therapy to 120-150% of the laboratory control (see PRECAUTIONS: Drug Interactions).While nefazodone did not alter the in vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, or verapamil, it is unknown whether displacement of either nefazodone or these drugs occurs in vivo. There was a 5% decrease in the protein binding of haloperidol; this is probably of no clinical significance.

Effect of Food - Food delays the absorption of nefazodone and decreases the bioavailability of nefazodone by approximately 20%.

Renal Disease - In studies involving 29 renally impaired patients, renal impairment (creatinine clearances ranging from 7 to 60 mL/min/1.73m²) had no effect on steady-state nefazodone plasma concentrations.

Liver Disease - In a multiple-dose study of patients with liver cirrhosis,the AUC values for nefazodone and HO-NEF at steady state were approximately 25% greater than those observed in normal volunteers.

Age/Gender Effects - After single doses of 300 mg to younger (18-45 years) and older patients (>65 years),C_max and AUC for nefazodone and hydroxynefazodone were up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 1 0 - 20%.A similar result was seen for gender, with a higher C_max and AUC in women after single doses but no difference after multiple doses.

Treatment with SERZONE should be initiated at half the usual dose in elderly patients, especially women (see DOSAGE AND ADMINISTRATION),but the therapeutic dose range is similar in younger and older patients.

During its premarketing development, the efficacy of SERZONE was evaluated at doses within the therapeutic range in five well-controlled, short-term (6-8 weeks) clinical investigations. These trials enrolled outpatients meeting DSM-III or DSM-IIIR criteria for major depression. Among these trials, two demonstrated the effectiveness of SERZONE, and two provided additional support for that conclusion.

One trial was a 6-week dose-titration study comparing SERZONE in two dose ranges (up to 300 mg/day and up to 600 mg/day [mean modal dose for this group was about 400 mg/day],on a BID schedule) and placebo. The second trial was an 8-week dose-titration study comparing SERZONE (up to 600 mg/day; mean modal dose was 375 mg/day),imipramine (up to 300 mg/day),and placebo, all on a BID schedule. Both studies demonstrated SERZONE, at doses titrated between 300 mg to 600 mg/day (therapeutic dose range), to be superior to placebo on at least three of the following four measures: 17-Item Hamilton Depression Rating Scale or HDRS (total score), Hamilton Depressed Mood item, Clinical Global Impressions (CGI) Severity score, and CGI Improvement score. Significant differences were also found for certain factors of the HDRS (eg,anxiety factor, sleep disturbance factor, and retardation factor).In the two supportive studies, SERZONE was titrated up to 500 or 600 mg/day (mean modal doses of 462 mg/day and 363 mg/day).In the fifth study, the differentiation in response rates between SERZONE and placebo was not statistically significant. Three additional trials were conducted using subtherapeutic doses of SERZONE.

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